Ancobon (Flucytosine) - Description and Clinical Pharmacology

DESCRIPTION

Ancobon (flucytosine), an antifungal agent, is available as 250 mg and 500 mg capsules for oral administration. Each capsule also contains corn starch, lactose and talc. Gelatin capsule shells contain parabens (butyl, methyl, propyl) and sodium propionate, with the following dye systems: 250 mg capsules - black iron oxide, FD&C Blue No. 1, FD&C Yellow No. 6, D&C Yellow No. 10 and titanium dioxide; 500 mg capsules - black iron oxide and titanium dioxide. Chemically, flucytosine is 5-fluorocytosine, a fluorinated pyrimidine which is related to fluorouracil and floxuridine. It is a white to off-white crystalline powder with a molecular weight of 129.09 and the following structural formula:

CLINICAL PHARMACOLOGY

Flucytosine is rapidly and virtually completely absorbed following oral administration. Ancobon is not metabolized significantly when given orally to man. Bioavailability estimated by comparing the area under the curve of serum concentrations after oral and intravenous administration showed 78% to 89% absorption of the oral dose. Peak serum concentrations of 30 to 40 µg/mL were reached within 2 hours of administration of a 2 g oral dose to normal subjects. Other studies revealed mean serum concentrations of approximately 70 to 80 μg/mL 1 to 2 hours after a dose in patients with normal renal function receiving a 6-week regimen of flucytosine (150 mg/kg/day given in divided doses every 6 hours) in combination with amphotericin B. The half-life in the majority of healthy subjects ranged between 2.4 and 4.8 hours. Flucytosine is excreted via the kidneys by means of glomerular filtration without significant tubular reabsorption. More than 90% of the total radioactivity after oral administration was recovered in the urine as intact drug. Flucytosine is deaminated (probably by gut bacteria) to 5-fluorouracil. The area under the curve (AUC) ratio of 5-fluorouracil to flucytosine is 4%. Approximately 1% of the dose is present in the urine as the α-fluoro-β-ureido-propionic acid metabolite. A small portion of the dose is excreted in the feces.

The half-life of flucytosine is prolonged in patients with renal insufficiency; the average half-life in nephrectomized or anuric patients was 85 hours (range: 29.9 to 250 hours). A linear correlation was found between the elimination rate constant of flucytosine and creatinine clearance.

In vitro studies have shown that 2.9% to 4% of flucytosine is protein-bound over the range of therapeutic concentrations found in the blood. Flucytosine readily penetrates the blood-brain barrier, achieving clinically significant concentrations in cerebrospinal fluid.

Pharmacokinetics in Pediatric Patients

Limited data are available regarding the pharmacokinetics of Ancobon administered to neonatal patients being treated for systemic candidiasis. After five days of continuous therapy, median peak levels in infants were 19.6 µg/mL, 27.7 µg/mL, and 83.9 µg/mL at doses of 25 mg/kg (N=3), 50 mg/kg (N=4), and 100 mg/kg (N=3), respectively. Mean time to peak serum levels was of 2.5 ± 1.3 hours, similar to that observed in adult patients. A good deal of interindividual variability was noted, which did not correlate with gestational age. Some patients had serum levels > 100 µg/mL, suggesting a need for drug level monitoring during therapy. In another study, serum concentrations were determined during flucytosine therapy in two patients (total assays performed =10). Median serum flucytosine concentrations at steady state were calculated to be 57 ± 10 µg/mL (doses of 50 to 125 mg/kg/day, normalized to 25 mg/kg per dose for comparison). In three infants receiving flucytosine 25 mg/kg/day (four divided doses), a median flucytosine half-life of 7.4 hours was observed, approximately double that seen in adult patients. The concentration of flucytosine in the cerebrospinal fluid of one infant was 43 µg/mL 3 hours after a 25 mg oral dose, and ranged from 20 to 67 mg/L in another neonate receiving oral doses of 120 to 150 mg/kg/day.

MICROBIOLOGY

Mechanism of Action

Flucytosine is taken up by fungal organisms via the enzyme cytosine permease. Inside the fungal cell, flucytosine is rapidly converted to fluorouracil by the enzyme cytosine deaminase. Fluorouracil exerts its antifungal activity through the subsequent conversion into several active metabolites, which inhibit protein synthesis by being falsely incorporated into fungal RNA or interfere with the biosynthesis of fungal DNA through the inhibition of the enzyme thymidylate synthetase.

Activity In Vitro

Flucytosine exhibited activity against Candida species and Cryptococcus neoformans. In vitro activity of flucytosine is affected by the test conditions. It is essential to follow the approved standard method guidelines.¹

Susceptibility Tests

Cryptococcus neoformans:

No interpretive criteria have been established for Cryptococcus neoformans. ¹

Candida:

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of yeasts to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method¹ with standardized inoculum concentrations and standardized concentrations of flucytosine powder. The MIC values should be interpreted according to the following criteria:

MIC(µg/mL)	Interpretation
≤4	Susceptible (S)
8-16	Intermediate (I)
≥32	Resistant (R)

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected. Because of other significant host factors, in vitro susceptibility may not correlate with clinical outcomes.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard flucytosine powder should provide the following MIC values:

Acceptable ranges of MICs (µg/mL) for control strains for 48-hour reference broth macrodilution testing:

Microorganism		MIC(µg/mL)	[% of data included]
Candida parapsilosis	ATCC 22019	0.12-0.5	[98.6%]
Candida krusei	ATCC 6258	4.0-16	[96.8%]

Acceptable ranges of MICs (µg/mL) for control strains for 24-hour and 48-hour reference broth microdilution testing:

	MIC (µg/mL) ranges for microdilution testing
	24-hour			48-hour
Microorganism	Range	Mode	% of Data Included	Range	Mode	% of Data Included
Candida parapsilosis ATCC 22019	0.06-0.25	0.12	99%	0.12-0.5	0.25	98%
Candida krusei ATCC 6258	4.0-16	8.0	98%	8.0-32	16	99%

Drug Resistance

Flucytosine resistance may arise from a mutation of an enzyme necessary for the cellular uptake or metabolism of flucytosine or from an increased synthesis of pyrimidines, which compete with the active metabolites of flucytosine (fluorinated antimetabolites). Resistance to flucytosine has been shown to develop during monotherapy after prolonged exposure to the drug.

Drug Combination

Antifungal synergism between flucytosine and polyene antibiotics, particularly amphotericin B has been reported in vitro. Ancobon is usually administered in combination with amphotericin B due to lack of cross-resistance and a reported synergistic activity of both drugs.